DESCRIPTION (APPLICANT'S ABSTRACT): Although our understanding of cancer has dramatically progressed, it still remains the leading cause of death, in the United States, after heart disease. The worldwide increased number of deaths from malignant tumors together with the failure of all "magic bullets" developed to prevent and/or cure these diseases brought us to look back at medicinal herbs. Ginkgo biloba is one of the most ancient trees and extracts from its leaves have been used in traditional medicine for several hundred years. Our research for the last decade has focused on understanding the function of the peripheral-type benzodiazepine receptor (PBR), an ubiquitous protein involved in intracellular cholesterol compartmentalization. PBR expression is dramatically increased in aggressive human breast cancer cells where its expression correlates with the increased cell proliferation and the aggressive phenotype of the cells. In preliminary studies we observed that the standardized extract o Ginkgo biloba leaves (EGB 761) inhibited PBR expression and cell proliferation in the aggressive human breast tumor cell line MDA-23 1, but not in a non-aggressive cell line. Using a gene expression array we found that EGB 761 treatment regulated the expression of specific gene products, including oncogenes, cell cycle regulators, apoptosis-related products, transcription factors, and growth factors, involved in various pathways regulating cell proliferation. These in vitro data were validated in an in vivo model where treatment with EGB 761 significantly inhibited the growth and PBR expression of MDA-231 cell xenografts in nude mice. Taken together, these data suggest that EGB 761 may exert cytostatic properties. It is our hypothesis that the cytostatic effect of EGB 761 is not confined to the MDA-231 cells but applies to other carcinogenic tumor cells. Our first specific aim is to validate these findings by examining the effect of EGB 761 on other aggressive breast cancer cell lines. The effect of EGB 761 on cell proliferation, apoptosis, cell cycle and gene expression will be studied in vitro. Its effect on primary tumor size, presence of metastases and vascularization in the tumor area will be studied in vivo in a cell xenograft nude mice model. Considering that PBR is also overexpressed in cancers such as gliomas, hepatomas, colon and prostatic carcinomas, our second aim is to examine the effects of EGB 761 on regulating the in vitro and in vivo proliferation and growth rates, respectively, of glioma, hepatoma, colon and prostatic carcinoma cells. These experiments should demonstrate if EGB 761 could be used to prevent and/or stabilize the progression of cancer.